Device and method for leakage testing of a connection between a rubber stopper and a corresponding drug container

ABSTRACT

The invention concerns the field of container closure integrity (CCI) and the testing of CCI and relates to a device and a method for providing a displacement of a rubber stopper for leakage testing of a connection between the rubber stopper and a corresponding drug container which can be used for storing drugs under sterile conditions and which is closed by said rubber stopper.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage entry of InternationalApplication Number PCT/EP2019/085748 filed under the Patent CooperationTreaty having a filing date of Dec. 17, 2019, which claims priority toU.S. Provisional Patent Application No. 62/780,493, having a filing dateof Dec. 17, 2018, European Patent Application No. 18213204.3 having afiling date of Dec. 17, 2018, European Patent Application No. 19165311.2having a filing date of Mar. 26, 2019, and European Patent ApplicationNo. 19200174.1 having a filing date of Sep. 27, 2017, which areincorporated herein by reference.

FIELD OF THE INVENTION

The invention concerns the field of container closure integrity (CCI)and the testing of CCI and relates to a device and a method for leakagetesting of a connection between a rubber stopper and a correspondingdrug container which can be used for storing drugs under sterileconditions and which is closed by said rubber stopper.

TECHNOLOGICAL BACKGROUND

WO 2015 108 423 A1 discloses an apparatus and method for testing peelstrength and leak tightness of a package comprising a peel seal. Thepackage has a peel seal. The apparatus comprises a receptacle forreceiving the package, a lid for closing the receptacle, the lid andreceptacle enclosing a chamber for holding the package, a movableelement arranged to be positioned in a first position and in a secondposition, a pump for reducing a gas pressure inside the chamber, and apressure sensor for determining the gas pressure inside the chamber. Inthe first position the chamber has a first volume that is larger than anouter volume of the package such that, in use, the peel seal of thepackage in the receptacle is free to release. In the second position,the chamber has a second volume that is complementary to the outer shapeof the package.

U.S. Pat. No. 8,316,697 B1 discloses an analytical instrument andassociated method for ascertaining gas transmission rates of atarget-analyte through a capped mouth of a bottle. The instrumentemploys a unique fixture that includes a selectively openable andcloseable enclosure defining a chamber, and a mounting post extendinginto the chamber. The post is configured and arranged to sealinglyengage an inner surface of a capped bottle neck, wherein mounting of acapped bottle neck onto the post sealingly separates the chamber into afirst compartment inside the mounted capped bottle neck and a secondcompartment outside the mounted capped bottle neck. The fixture isconfigured and arranged with passageways for introducing a pressurizedtarget-analyte-containing fluid into the first compartment of thechamber and flushing the second compartment of the chamber with atarget-analyte-free fluid.

DE10 2006 047 040 B3 discloses an apparatus having a mechanical retainerfor fixing a test vial, and a container for restricting a test area fromenvironment and atmosphere. The test vial is arranged within thecontainer, where a test gas e.g. helium, flows through the container. Aspacer is provided with different characteristics, thickness anddiameters for introducing a distance between a definite stopper positionand a variable stopper position so that a leakage is generated forguiding the test gas from an inner area of the vial to a leakage tester.

A drug container, which can be used for storing drugs under sterileconditions and which is closed by a rubber stopper, can e.g. be a vialor a cartridge.

A vial, also known as a phial or flacon, is a small glass or plasticvessel or bottle which is often used to store medication as liquids oras solids such as powders or capsules. They can also be used asscientific sample vessels. In particular, vials are used as storage forsmall quantities of a solid material or a liquid used in pharmaceutical,medical or scientific applications, such as microbiology molecularbiology or genetic applications.

A cartridge can be used to store compositions in liquid form.

A drug container usually comprises a top-side opening which can besealed by a correspondingly shaped rubber stopper.

It is often of significant importance, e.g. in medical applications, toensure integrity of the closure, in particular of the sealing providedby the rubber stopper, to avoid any contamination of the product storedin the drug container. During production, packaging or transport, or anyother handling, the drug container may be exposed to an externalinfluence, such that the rubber stopper may be displaced with respect tothe drug container from its initial sealing position in an openingdirection over such a distance that the container starts leaking.

Therefore it is desirable to have an indication of the tolerance of theflexible part, that is the rubber stopper, against movement until a leakoccurs. In particular, it would be beneficial to have a possibility toassess whether a rubber stopper which has been extracted from itsinitial sealing position by a predetermined threshold distance, hereinalso called predetermined threshold travel or predetermined thresholdvalue, still prevents leakage. There was a need for testing CCI of aconnection between a rubber stopper and a corresponding drug containerand for examining the quality of a combination of a rubber stopper and acorresponding drug container.

The present invention provides means for CCI testing in form of a deviceand a method for providing a displacement of a rubber stopper forleakage testing of a connection between the rubber stopper and acorresponding drug container. It is a further object of the presentinvention to provide the possibility of examining the quality of acombination of a drug container and a rubber stopper.

The above objects are solved by a device for providing a displacement ofa rubber stopper for leakage testing of a connection between a rubberstopper and a corresponding drug container comprising the featuresaccording to the device claims. Furthermore, the above objects aresolved by a method for providing a displacement of a rubber stopper forleakage testing of a connection between the rubber stopper and acorresponding drug container, preferably a vial or a cartridge,comprising the features according to the method claims.

SUMMARY OF THE INVENTION

Subject of the invention is a device (1) for providing a displacement ofa rubber stopper (2), which is inserted into the regular opening (30) ofa drug container (3), relative to the drug container (3) in an openingdirection (32) for testing of a connection between the rubber stopper(2) and the corresponding drug container (3), the device (1) comprising

-   -   a test medium supply (13) for exposing a connection region of        the drug container (3) and the rubber stopper (2) to a test        medium    -   a detection unit (6) for detecting the presence of test medium        that has passed through a regular opening (30) of the drug        container (3) due to a leakage between the connection of the        rubber stopper (2) and the drug container (3)    -   a support member (70)    -   a movement member (71),

a drug container receptacle (5) with the container (3) received in thedrug container receptacle (5), wherein

the support member (70) supports the movement member (71),

the movement member (71) is movable relative to the support member (70)in a movement direction (72) which is parallel to the opening direction(32) of the rubber stopper (2), and

the movement member (71) extends into the drug container receptacle (5)for the displacement of the rubber stopper (2) such that part of themovement member (71) can be inserted into the drug container (3) througha communication hole (31) which is provided at drug container (3) apartfrom its regular opening (30) for enabling fluid communication of theinterior of the drug container (3) and the exterior of the drugcontainer (3).

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will be more readily appreciated by reference tothe following detailed description when being considered in connectionwith the accompanying drawings in which:

FIG. 1 is a schematic sectional view of a device for providing adisplacement of a rubber stopper for leakage testing of a connectionbetween the rubber stopper and a corresponding drug container accordingto an exemplary embodiment;

FIG. 2 is another schematic sectional view of the device of FIG. 1;

FIG. 3 is a schematic sectional view of a device for providing adisplacement of a rubber stopper for leakage testing of a connectionbetween the rubber stopper and a corresponding drug container accordingto a further embodiment;

FIG. 4 is another schematic sectional view of the device of FIG. 3;

FIG. 5 is a schematic sectional view through the drug container of FIG.3 perpendicular to an opening direction;

FIG. 6 is a schematic sectional view through the drug container of FIG.4 perpendicular to an opening direction;

FIG. 7 is another schematic sectional view of the device of FIG. 3;

FIG. 8 is another schematic sectional view of the device of FIG. 3;

FIG. 9 is another schematic sectional view of the device of FIG. 3;

FIG. 10 is a schematic sectional view of a device for providing adisplacement of a rubber stopper for leakage testing of a connectionbetween the rubber stopper and a corresponding drug container accordingto a further embodiment;

FIG. 11 is another sectional view of the device of FIG. 10;

FIG. 12 schematically shows another exemplary embodiment of a device forproviding a displacement of a rubber stopper for leakage testing of aconnection between the rubber stopper and a corresponding drugcontainer;

FIG. 13 shows the device of FIG. 12 having a drug container inserted inits drug container receptacle;

FIG. 14 is a photograph of an exemplary embodiment of a device forleakage testing of a connection between a rubber stopper and acorresponding drug container;

FIG. 15 schematically shows another exemplary embodiment of a device forleakage testing of a connection between a rubber stopper and acorresponding drug container comprising a tempering device;

FIG. 16 schematically shows a device according to another preferredembodiment comprising a temperature sensor;

FIG. 17 schematically shows a device according to FIG. 16 comprising atempering device according to FIG. 15;

FIG. 18 shows a perspective bottom view of another embodiment of thedevice;

FIG. 19 shows a perspective top view of the embodiment of the deviceaccording to FIG. 18;

FIG. 20 shows a perspective top view of the main body of the embodimentof FIG. 14;

FIG. 21 shows a perspective top view of another embodiment of thedevice; and

FIG. 22 shows a perspective top view of the embodiment of the deviceaccording to FIG. 21 in a disassembled state.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the following, the invention will be explained in more detail withreference to the accompanying figures. In the figures, like elements aredenoted by identical reference numerals and repeated description thereofmay be omitted in order to avoid redundancies.

Preferably, the drug container (3) is a drug container (3) which can beused for storing drugs under sterile conditions and which is closed bythe rubber stopper.

The drug container (3) can be a vial or a cartridge, preferably it is avial.

Preferably, the drug container (3) is a non-pressurized container.

In FIG. 1, a schematic sectional view of a device (1) and of the devicefor providing a displacement of a rubber stopper for leakage testing ofa connection between the rubber stopper (2) and a corresponding drugcontainer (3) according to a first embodiment is shown.

The support member (70) supports the movement member (71). Preferably,the support member (70) and the displacement member (71) comprisecomplementarily formed threads (700, 710) engaging with each other,which are configured such that a rotation of the movement member (71)relative to the support member (70) results in a linear travel (73) ofthe movement member (71) relative to the support member (70) in themovement direction (72).

By means of the engaging threads (700, 710), when rotating the movementmember (71) relative to the support member (70), the movement member(71) performs a helical movement predetermined by the configuration ofthe threads (700, 710), in particular by the lead of the threads (700,710), as will be described in more detail below.

Preferably, the support member (70) comprises an internal thread (700)and the movement member (71) comprises a threaded rod (715), the thread(710) of the threaded rod (715) is in engagement with the internalthread (700) of the support member (70).

In principle, the lead of the threads (700, 710) can be chosen withrespect to the size of the drug container (3) and its rubber stopper(2), so for example the larger the drug container (3) and the rubberstopper (2), the larger the lead may be chosen; or for example thelarger the possible linear travel (73), which can be realized withrespect to the dimensions of the rubber stopper (2) and the regularopening (30), the larger the lead may be chosen. Another criteria tochoose the lead can be a predetermined threshold value to which the leadmust correspond, for example the lead can be the predetermined thresholdvalue or the lead can be a fraction of the predetermined thresholdvalue.

Preferably the lead of the threads (700, 715) is in the range of from0.01 mm to 10 mm, more preferably of from 0.1 mm to 8 mm, even morepreferably of from 0.2 mm to 8 mm.

In one embodiment for rather smaller drug containers, the lead ispreferably of from 0.1 mm to 5 mm, more preferably from 0.2 to 4 mm,even more preferably from 0.2 to 3 mm, especially from 0.2 to 2 mm.

In another embodiment for rather larger drug containers, the lead ispreferably of from 0.5 mm to 10 mm, more preferably from 0.75 to 8 mm,even more preferably from 1 to 6 mm.

In a specific embodiment the lead is 1 mm.

The “lead” is to be understood as the rise, that is as the linear travel(73) the movement member (71) makes per revolution about 360° relativeto the support member (70).

A communication hole (31) is provided at the bottom of the drugcontainer (3). The movement member (71) extends into the drug containerreceptacle (5) for the displacement of the rubber stopper (2) such thatpart of the movement member (71) can be inserted into the drug container(3) through a communication hole (31) which is provided at drugcontainer (3) apart from its regular opening (30) for enabling fluidcommunication of the interior of the drug container (3) and the exteriorof the drug container (3). Preferably, the communication hole (31)comprises an extension such that at least the threaded rod (715) of themovement member (71), or the threaded rod (715) and the support member(70), can be inserted at least in an insertion direction by using aninsertion orientation of the threaded rod (715) and/or of the supportmember (70).

Preferably, the movement member (71) contains a collar section (713) formaking contact with an insertion section (21) of the rubber stopper (2).

Preferably, the collar section (713) is arranged at an end of thethreaded rod (715), wherein preferably, the collar section (713) isrotatably connected to the threaded rod (715).

To allow pushing the insertion section (21) through the opening (30),the collar section (713) comprises a diameter (702) smaller than theinner diameter of the opening (30) of the drug container (3) which isintended to be tested via the device (1).

The collar section (713) can also have a form different from a circularshape, as long as the maximum lateral extension, that is the diameter(702), of the collar section (713) is smaller than the inner diameter ofthe opening (30).

The dimension of the device (1) and of its members are adapted andchosen according to the dimensions of the drug container (3) and therubber stopper (2) corresponding to the drug container (3) as explainedherein.

In case that the drug container (3) is a vial, typical dimensions ofvials are known to the skilled person and are for example as stated inTable 10.

TABLE 10 d1 d2 Size designation of vial [mm] [mm]  2R 16 13  6R 22 2020R 30 20

d1: outer Diameter of the body of the vial

d2: maximum diameter of the neck portion (33) of the vial

Preferably, the communication opening (31) is in form of a hole or of aslot.

The communication opening (31) may be arranged at the bottom of the drugcontainer (3); also the whole bottom of the drug container (3) can becut off to provide said communication opening (31). This communicationopening (31) is an artificial opening that was introduced into the drugcontainer (3) only for the purpose of testing the container closureintegrity.

In the exemplary embodiment displayed in FIG. 1, the drug container (3)is provided in form of a vial.

The device (1) further comprises a test medium supply (13) for exposinga connection region of the drug container (3) and the rubber stopper (2)to a test medium, this exposure can be done from the exterior or fromthe interior (36) of the drug container (3).

The test medium may be but is not limited to a test gas, preferably thetest gas is a rare gas such as helium or argon, or hydrogen, morepreferably the test gas is helium.

Furthermore, the device (1) comprises a detection unit (6) for detectingthe presence of test medium that has passed through the regular opening(30) of the drug container (3) due to a leakage between the connectionof the rubber stopper (2) and the drug container (3).

In this exemplary embodiment, the detection unit (6) is configured todetect test medium which has passed through the regular opening into theinterior (36) of the drug container (3). Therefore, the detection unit(6) may be in fluid communication with the interior (36) viacommunication opening (31). The fluid communication may be preferablyprovided by a connection channel (11) extending in an optional main body(10) of the device (1) from the drug container receptacle (5) towardsthe detection unit (6).

Preferably, the detection unit (6) comprises a mass spectrometer.

Drug container receptacle (5) may optionally comprise one or moresealings (50) for sealing the connection channel (11) and/or areceptacle chamber (52) against the exterior of the device (1) when thedrug container (3) is correctly inserted into the drug containerreceptacle (5). Preferably, one or more guidings (53), preferably guiderings, are arranged in the drug container receptacle (5) for guiding thedrug container (3) with respect to the receptacle (5). In a preferredembodiment, the sealings (50) may also provide guiding of the drugcontainer (3), more preferably the sealings (50) may be identical withthe guidings (53).

The one or more sealings (50) may divide the device (1) and the drugcontainer receptacle (5) into an upstream portion, which is above theone or more sealings (50) and into a downstream potion, which is belowthe sealings (50). Preferably, thereby, the receptacle chamber (52) ofthe drug container receptacle (5) being in fluid communication with theconnection channel (11) may be formed by the lower or inner part of thereceptacle (5), one of the one or more sealings (50) and the wall of thedrug container (3).

Device (1) can comprise a travel determining unit. For determiningand/or acquiring the linear travel (73) of the movement member (71)relative to the support member (70), The linear travel (73) of themovement member (71) relative to the support member (70) may bedetermined and/or acquired by means of detecting a cumulated angle ofrotation of the movement member (71) relative to the support member(70). According to an exemplary embodiment, in this regard, the traveldetermining unit may comprise an encoder, preferably an absoluteencoder.

Furthermore, a positioning unit (15) may optionally be provided in thedrug container receptacle (5) for providing a stop position defining amaximum insertion depth of the drug container (3) into the drugcontainer receptacle (5). Preferably, the positioning unit may bearranged to prevent closing of the connection channel (11) by the drugcontainer (3) and/or the rubber stopper (2).

In some embodiments of the invention the one or more sealings (50), theone or more guidings (53), and/or a portion of an inner wall of the drugcontainer receptacle (5) may be adapted to function as the positioningunit (15). Alternatively, the sealings (50), and/or the guidings (53)may be provided separate to positioning unit (15).

In some embodiments, the positioning unit (15) is a part which isremovable from the device and can be placed on the drug container (3).

According to yet another embodiment, the one or more guidings (53)and/or the positioning unit (15) may be part of the device (1), whereinpreferably, the device (1) comprises a guiding section forming theguiding and/or a positioning section forming the positioning unit (15),wherein preferably, the positioning section and/or the guiding sectionmay be formed integrally with the device (1), preferably with thesupport member (70) and/or the movement member (71).

In some embodiments, the sealing (50), the guiding and/or thepositioning unit may comprise an O-Ring.

According to a further embodiment, the device (1) may comprise anadaptor which is compatible with a common leak detection system. Inparticular, the adaptor might be a flange or a ring.

Alternatively or in addition, the optionally provided sealing (50),guiding and/or positioning unit may be made of a flexible material,preferably a material selected from an elastomer, such as rubber, latex,or silicone.

Preferably, the support member (70) comprises a support section (703).

Preferably, the support member (70) can be attached and/or fixed to amain body (10) of a device (1) for leakage testing as described below bymeans of the support section (703).

Alternatively, the support member (70) is adapted for supporting thedevice (1) against the drug container (3), as will be described in moredetail with respect to FIGS. 3 to 11 below.

Moreover, the device (1) may comprise an optional down-holding unit(16), which preferably is detachable and which may exert a force ontothe drug container (3) in direction of the positioning unit (15),preferably by means of biasing the displacement unit. Thereby, the drugcontainer (3) may be held in position with respect to the main body(10). Preferably, the drug container (3) can be fixed in its positionwith regard to the main body (10) by means of the positioning unit (15)and the down-holding unit (16).

Preferably, the positioning unit (15), preferably in combination withthe down-holding unit (16), prevents a repositioning of the container(3) even when a pressure difference is applied.

Preferably, the down holding unit (16) is adapted to be attached and/orto contact a shoulder (35) of the drug container (3).

Preferably, the device (1) further comprises a housing (9) whichprovides a chamber into which test medium indicated via reference sign(4) may be introduced from a test medium supply (13). The housing (9) ispreferably removable. Preferably, the housing (9) comprises in additionan outlet (not shown) for pressure control inside the chamber providedby the housing (9).

Device (1) may comprise a movement unit (8) for moving the movementmember (71) in the moving direction (72).

The movement unit (8) may comprise a gear wheel (80) which is inengagement with a plurality of radially outwards extending teeth (716)distributed in a circumferential direction at an engagement section(717) of the movement member (71).

Preferably, the plurality of radially outwards extending teeth (716) isdistributed evenly in a circumferential direction at the engagementsection (717).

Preferably, the engagement section (717) is arranged at the end of thethreaded rod (715) opposite to the end at which the collar section (713)is arranged.

Preferably, the gear wheel (80) comprises a width greater than a maximumlinear travel (73) of the movement member (71), and/or the engagementsection (717) comprises a width greater than a maximum linear travel(73) of the movement member (71), as shown in FIG. 1.

The movement unit (8) may comprise an actuator for moving the movementmember (71) or the support member (70), respectively, in the movingdirection (72).

Preferably, the actuator is an electric servomotor and/or a steppermotor.

The movement unit (8) may further comprise an encoder for detecting anangular position and/or the cumulated angle of rotation of the movementmember (71) and/or the movement unit 8, preferably the gear wheel (80).

Preferably, the encoder is an absolute encoder.

Further subject of the invention is a method for providing adisplacement of a rubber stopper (2) for leakage testing of a connectionbetween a rubber stopper (2) and a corresponding drug container (3),comprising

a) providing a device (1) according to the invention as defined herein,also with all of its embodiments,

b) providing a drug container (3) with a communication opening (31) forenabling fluid communication of an exterior of the drug container (3)with the interior (36) of the drug container (3) apart from its regularopening (30),

c) closing the regular opening (30) of the drug container (3) with therubber stopper (2),

d) inserting the drug container (3) into the drug container receptacle(50) of the device (1),

e) exposing either the exterior of the drug container (3) or,alternatively, the interior (36) of the drug container (3) at least at aconnection region of the drug container (3) and the rubber stopper (2)inserted into the regular opening (30) of the drug container (3) to atest medium,

and

f) displacing the rubber stopper (2) relative to the drug container (3)in an opening direction (32) for a chosen distance while measuring anypresence of the test medium either in the interior (36) or,alternatively, in the exterior of the drug container (3) that has passedthrough the regular opening (30), wherein

g) the rubber stopper (2) is displaced relative to the drug container(3) by means of the movement member (71).

In one embodiment of the invention, the interior (36) of the drugcontainer (3) is filled with test medium.

In another embodiment of the invention, the exterior around the rubberstopper (2) comprises test medium. In this case the exterior around therubber stopper (2) can be placed in the interior of a container or ahousing (9) which is filled with test medium.

The chosen distance can be any chosen distance, for example apredetermined threshold distance, or a distance until presence of thetest medium either in the interior (36) or, alternatively, in theexterior of the drug container (3) passed through the regular opening(30) is detected.

Preferably, at least the threaded rod (715) of the device (1) ispartially inserted into the drug container (3) through the communicationopening (31). In addition, parts or all of the support member (70)and/or further parts or all of the movement member (71) besides thethreaded rod (715) can be inserted into the drug container (3) throughthe communication opening (31). Said insertion is done at least in apredetermined insertion direction by using a predetermined insertionorientation of the threaded rod (715) and/or of the support member (70)and/or of the movement member (71) and/or their respective parts.

After having at least partially inserted the threaded rod (715) into thedrug container (3) and after having closed the regular opening (30) withthe rubber stopper (2), the movement member (71) may be rotated relativeto the support member (70). Thereby the rubber stopper (2) is displacedin the opening direction (32).

Preferably, the support member (70) and the movement member (71) arearranged in a screwed-in position relative to each other as shown ine.g. FIG. 3. This preferably is be done before partial insertion of themovement member (71) into the drug container (3). Preferably, themovement member (71) and the support member (70) of device (1) aredimensioned in such a way that in the screwed-in position, the movementmember (71), in particular the end face of the collar section (713) ofthe threaded rod (715) is separated from the end face of the insertionsection (21) of the rubber stopper (2) by a certain preferablypredefined distance as shown in FIG. 3.

Prior or subsequent to partially inserting the movement member (71) ofthe device (1) into the drug container (3) through communication opening(31) as described above, the regular opening (30) is closed with therubber stopper (2) by insertion of the rubber stopper (2) into theregular opening (30) until the collar (20) of the rubber stopper (2)makes contact with the neck portion (33) of the drug container (3). Asthe movement member (71) of the device (1) is inserted thoughcommunication opening (31), hence, the rubber stopper (2) can becompletely inserted into the regular opening (30) such that its collar(20) is in contact with collar (37) of the drug container (3).

For reaching an initial position, the movement member (71) may berotated relative to the support member (70) so that the movement member(71), in particular the end face of the collar section (713) of thethreaded rod (715), just makes contact with the end face of theinsertion section (21) of the rubber stopper (2) without moving therubber stopper (2). This reaching of the initial position can already bedone while the connection region of the drug container (3) and therubber stopper (2) is exposed to the test medium.

In FIG. 1, the above described initial position is shown.

Now, exposure of the connection region of the drug container (3) and therubber stopper (2) to the test medium and monitoring whether test mediumpasses through regular opening (30) may be started if said exposure hadnot already been started before or during the reaching of the initialposition. Then, the movement member (71) may be rotated relative to thesupport member (70) preferably while detecting the cumulated angle ofrotation of the movement member (71) relative to the support member(70), preferably starting from the initial position. With other words,the cumulated angle of rotation is set to zero at the beginning,preferably at the initial position, and the cumulated angle is a sum ofthe rotation the movement member (71) performs via its helical movementrelative to the support member (70).

During the rotation of the moving member (71) against the support member(70) the ongoing monitoring for test medium that may pass through theregular opening (30) will reveal for example whether a leakage hasoccurred until the predetermined threshold distance has been reached,or, alternatively, the distance is determined until passing of the testmedium (4) through the regular opening (30) occurs.

Therefore the method may further comprise acquiring the linear travel(73) of the rubber stopper (2) or of the movement member (71),respectively, by means of detecting the cumulated angle of rotation incombination with the lead of the threads (700, 715).

Preferably the linear travel (73) of the movement member (71) startingfrom the initial position is acquired by multiplication of the detectedcumulated angle of rotation by the lead of the threads (700, 715), thelatter having the unit “travel per degree of rotation”, preferablymm/360°. Hence, the helical movement may be divided in a rotationalmovement about an axis parallel to the opening direction (32), and alinear travel (73) parallel to the opening direction (32). It is alsopossible that said linear travel is be detected directly by a respectivedetecting device preferably being in communication with and/orintegrated in the travel determining unit.

A predetermined threshold travel in the opening direction (32) of therubber stopper (2) from a position in which the collar (20) makescontact with the collar (37) can be set for example by regulatoryauthorities that set standards for CCI. The method of instant inventionallows for testing the CCI in case of displacement of the rubber stopper(2) by a predetermined threshold travel smaller than the maximumpossible linear travel (73) of the movement member (71) starting fromthe initial position. As the linear travel 73 is defined herein as thetravel distance of the rubber stopper (2) starting from the initialposition, it corresponds to the linear travel (73) of the movementmember (71) starting from the initial position. Hence, the linear travel(73) of the movement member (71) may be used for comparison with thepredetermined threshold travel of the rubber stopper (2).

Furthermore, a boundary travel may be determined as being the lineartravel (73) at which test medium (4) having passed through the regularopening (30) is detected for the first time.

Optionally, the boundary travel may then be compared to a predeterminedthreshold travel in order to determine whether the boundary travel issmaller, equal or greater than the predetermined threshold travel. Oroptionally the linear travel (73) can also be stopped when thepredetermined threshold travel is reached in case that no presence ofthe test medium (4) has been detected having passed through the regularopening (30) until the predetermined threshold travel has been reached.

So the boundary travel shall be greater than the predetermined thresholdtravel for positive evaluation of the connection of the testedcombination of drug container (3) and rubber stopper (2), that is forpositive evaluation of CCI. For example, the predetermined thresholdtravel may have been set to 1 mm so the boundary travel shall be greaterthan 1 mm for positive evaluation of CCI. According to an exemplary leadof 1 mm per 360° of rotation, hence, the movement member (71) at leasthas to be rotated about 1.0 revolutions without detection of test mediumfor a positive result of CCI.

Hence, by detection of the angle of rotation as described above, asimple and precise detection of the linear travel 73 may be achieved.

FIG. 2 shows a position of the rubber stopper (2) at which test mediumhas been detected by the detection device (6). As can be seen, therubber stopper (2) has been moved by the movement member (71) in themovement direction (72), which corresponds to the opening direction(32), by an amount of the linear travel (73).

Preferably, for the leakage testing of a connection between a rubberstopper (2) and a corresponding drug container (3), the drug container(3) is inserted into the drug container receptacle (5) of device (1),with device (1) as defined herein, also with all its embodiments.

Depending on the embodiment of device (1) and obviously on theembodiment of the method for leakage testing, the device (1) can beconfigured in such a way the drug container (3) is inserted into thedrug container receptacle (5) in an upright position, that is with thebottom of the drug container (3) first, as displayed exemplary inFIG. 1. In this case preferably the exterior of the drug container (3)at least at a connection region of the drug container (3) and the rubberstopper (2) inserted into the regular opening (30) of the drug container(3) is exposed to test medium (4).

In another embodiment of device (1) and obviously of the method forleakage testing, the device (1) can be configured in such a way the drugcontainer (3) is inserted into the drug container receptacle (5) headon, that is with the neck portion (33) first, as displayed exemplary inFIGS. 10 and 11. In this case preferably the interior (36) of the drugcontainer (3) at least at a connection region of the drug container (3)and the rubber stopper (2) inserted into the regular opening (30) of thedrug container (3) is exposed to test medium (4),

In both cases, whether the drug container (3) is inserted into the drugcontainer receptacle (5) bottom first or head on, any test mediumpassing through the regular opening (30), that is in case of the leakagetesting by way of a leakage between the rubber stopper (2) and the drugcontainer (3), is passing preferably through the drug containerreceptacle (5), in particular through the receptacle chamber (52);preferably leaving the device (1) through the connection channel (11)and is preferably detected by the detection unit (6).

FIG. 3 is a schematic sectional view of a device (1) for leakage testingof a connection between a rubber stopper (2) and a corresponding drugcontainer (3) according to another embodiment. The device (1) in largepart corresponds to the device (1) shown in FIG. 1. In this embodiment,contrary to FIG. 1, the threaded rod (715) and the support member (70)are inserted into the drug container (3) by using a predeterminedinsertion orientation of the threaded rod (715) and in particular of thesupport member (70) as shown in this figure.

As can be seen, the support member (70) comprises an insertionorientation, here facing to the right with respect to the orientation ofdevice (1) in FIG. 3. The communication opening (31) comprises anextension such that, in the insertion orientation, the support member(70) can be inserted into the drug container (3) by pushing the drugcontainer (3) into the drug container receptacle (5) until the drugcontainer (3) abuts against the positioning unit (15).

With other words, in this embodiment, the support member (70) is merelyattached to the threaded rod (715) of the movement member (71) viathread (700) but is not connected to the main body (10).

Preferably, movement member (71) is positioned via engagement of analignment section (719), which is here optionally formed as an alignmentpin, of the movement member (71) with a positioning section (100) of themain body (10), here formed as optional positioning hole.

According to this exemplary embodiment, the support member (70) isadapted and formed for being engaged with the drug container (3). Bymeans of this engagement, the device (1) is supported against the drugcontainer (3).

In this regard, the support member (70) has to be brought into aengaging position with respect to the drug container (3). As a firststep after insertion of the drug container (3) in the insertionorientation, the movement member (71) has to be rotated. As the supportmember (70) is only engaged with the threaded rod (715), by rotation ofthe same, also the support member (70) is correspondingly rotated.

Preferably, the threads (700, 715) are formed as self-locking threads toensure rotation of the support member (70) when moving the movementmember (71).

The support member (70) is rotated until an abutment section (704) abutsagainst an inner wall (310) of the communication opening (31) as shownin FIG. 4.

The latter can be achieved as the abutment section (704) is arrangedeccentrically to the threaded rod (715), that is the longitudinal axisof the threaded rod (715), as can be seen in FIG. 5, which shows aschematic sectional view through the drug container (3) perpendicular tothe opening direction (32), hence to the longitudinal axis of thethreaded rod (715).

In FIG. 5, the support member (70) is positioned in the insertionorientation as shown in FIG. 3. Here, the eccentric abutment section(704) is distanced from the inner wall (310) of communication opening(31).

FIG. 6 schematically shows a further sectional view which substantiallycorresponds to FIG. 5, wherein here the support member (70) is orientedas shown in FIG. 4. By rotation of the threaded rod (715) and hence thesupport member (70), the abutment section (704) made contact with theinner wall (310). Hence, by further rotation of the threaded rod (715),the support member (70) moves downwards, that is against the movementdirection 72, until a support section (703) of the support member (70)makes contact with the drug container (3), as shown in FIG. 7.

Further rotation of the movement member (71) now causes to adisplacement of the movement member (71) in the movement direction (72)until the collar section (713) makes contact with the end surface of theinsertion section (21) of the rubber stopper (2), as can be taken fromFIG. 8.

This position, as shown in FIG. 8, constitutes the initial positionaccording to this exemplary embodiment. Further rotation of the movementmember (71) results in a displacement of the rubber stopper (2) in themovement direction (72), hence, causes linear travel (73) of the rubberstopper (2).

In FIG. 9, a further sectional view of the device shown in FIGS. 3 to 8is shown, in which the rubber stopper (2) has reached the boundarytravel at which test medium (4) has been detected for the first time viadetection unit (6).

FIG. 10 is a schematic sectional view of a device (1) for leakagetesting of a connection between a rubber stopper (2) and a correspondingdrug container (3) according to another embodiment. Here, the drugcontainer (3) is inserted with its neck portion (33) into the drugcontainer receptacle (5), with the neck portion (33) facing the bottomof drug container receptacle (5). Device (1) has a substantially similarsetup as described with regard to FIGS. 3 to 9.

Here, first, the drug container (3) having its regular opening (30)sealed via the rubber stopper (2) can be inserted head on into the drugcontainer receptacle (5) until the rubber stopper (2) abuts against thebottom of the drug container receptacle (5).

In a subsequent step, the displacement device 7 can be inserted into thecommunication opening (31) analogously but with vice versa direction tothe description with regard to FIG. 3.

Next, contact of the support member (70) via support section (703) withthe drug container (3) may be established analogously to as describedwith regard to FIGS. 4 to 9.

Thereby, the device (1) comprises the initial position being theposition as shown in FIG. 10.

Preferably, a detachable movement unit 8 may be provided, which inaddition may provide positioning and/or alignment of the movement member(71) with regard to a least a radial orientation with respect to theopening direction 32, that is to the longitudinal axis of the main body(10).

The movement unit (8) may be part of the device (1) or may be providedas a separate part.

Here, the optional test medium supply (13) is adapted to fill testmedium (4) into the interior (36) of the drug container (3) via thecommunication opening (31).

FIG. 11 schematically shows another sectional view of the device of FIG.10, wherein the movement member (71) has been rotated with respect tothe support member (70) such that the support member (70) has beendisplaced in the movement direction (72). Thereby, the support member(70) has shifted up the drug container (3) in the movement direction(72). As the movement member (71) pressed the rubber stopper (2)downwards, the rubber stopper (2) and the drug container (3) have beendisplaced to each other by linear travel 73.

Again, leakage testing can be performed as described with respect to theprevious embodiments.

With other words, in this exemplary embodiment, again, the movementmember (71) is displaced relative to the support member (70) by rotationof the movement member (71). As the rubber stopper (2) rests on thebottom of the drug container receptacle (5), by rotation of the movementmember (71), the support member (70) and hence the drug container (3) isdisplaced relative to the rubber stopper (2).

The device (1) also may preferably comprise a test medium supply (13)and/or a housing (9).

When leakage at the connection of regular opening (30) and rubberstopper (2) occurs, test medium can flow from the interior 36 of drugcontainer (3) to the connection channel (11) and further on to thedetection unit 6.

The collar section (713) may contain a contact area (718), which is thearea of the collar section which is in contact with eth rubber stopper(2), comprising a material having a low coefficient of friction againstthe rubber stopper (2), preferably equal to or smaller than 0.3, morepreferably equal to or smaller than 0.25, even more preferably equal toor smaller than 0.15 against the rubber stopper (2).

Preferably, the contact area (718) is a polymer such as a thermoplast orduroplast, examples are POM, PET, PVDF, or PEEK.

The contact area (718) may be provided in the form of a coating, and/orin the form of a separate part, for instance a sliding ring or slidingdisc.

This contact area should facilitate the rotation of the movement member(71) relative to the rubber stopper (2).

The support member (70) may contain a contact area (705) comprising amaterial having a high coefficient of friction against glass, preferablyequal or greater than 0.4, more preferably equal or greater than 0.5,even more preferably equal or greater than 0.6 against glass.

When rotating the movement member (71) relative to the support member(70), the contact area (705) due to a sufficiently high friction betweenthe support member (70) and the drug container (3), contributes tosubstantially avoiding or minimizing a movement, e.g. a slipping, of thesupport member (70) relative to the drug container (3).

Preferably, a housing (9) covers the top of the main body (10) therebyproviding a sealed space inside the housing (9), into which test medium(4) is inserted via the test medium supply (13).

An according device (1) can be derived from PCT/EP2018/074731 withfiling date 13 Sep. 2018, which is incorporated herewith by reference inits entirety.

FIGS. 12 and 13 schematically show a device (1), which comprisesintegrated measures to act as positioning unit (15). In this case, thepositioning unit (15) could be a protrusion, preferably a rim on theinside of the inner wall of the drug container receptacle (5).

The positioning unit (15) may be of the same or a different materialthan the sealing (50). In one embodiment of the invention, thepositioning unit is made of the same material as the sealing. In anotherpreferred embodiment, said material is a flexible material, such as anelastomer, for example selected from rubber, latex, or silicone. In afurther embodiment, the positioning unit is made from a rigid material,such as plastic, metal, or a rigid composite material.

Alternatively, the positioning unit (15) unit may be made of the same ordifferent material as the wall of the drug container receptacle (5). Ifthe positioning unit is integral to the drug container receptacle (5),it is preferred that it is made of the same material as the drugcontainer receptacle (5) and/or the main body (10).

FIG. 15 shows an embodiment wherein the positioning unit is made of amaterial different from the material of the wall of the drug containerreceptacle (5), preferably of a material used for sealing so that theposition unit acts simultaneously as sealing (50).

The housing (9) and/or the main body (10) might comprise any suitablematerial. Particularly suitable materials include, but are not limitedto metals, metal alloys or plastic, more preferably steel, aluminum orplastic. The device (1) may be adapted and/or sized for one specifictype of drug container (3) defined by its dimensions. Alternatively, thepositioning unit (15) and/or sealing (50) and/or the guidings (53) maybe exchangeable to allow adaptation of the device (1) to different sizesor shapes of drug containers. If the device (1) is adaptable todifferent sizes of containers or to different container shapes, it ispreferred that the exchangeable sealing (50) and/or positioning unit(15) and/or guidings (53) are made of the same material. Preferably, inthis case positioning unit (15) is adapted to also function as sealing(50).

It is important that the drug container receptacle (5), the main body(10) and/or the housing (9) are configured to withstand a pressuredifference between the sealed inside and the external environment whenthe testing conditions are applied.

In another preferred embodiment, the device (1) comprises means to beconnected to a computing device.

As shown in FIG. 19 an embodiment of the main body (10) of the devicehas a step (1000) on the outer circumference. The step (1000) in theupper part of the main body (10). In particular, the outer diameter ofthe main body (10) is smaller in the upper part. One usage of this step(1000) will be described later with reference to FIGS. 21 and 22.

In FIGS. 18 and 19 an embodiment of the main body (10) of the device isshown, wherein the main body (10) comprises an ejector punch (111). Theejector punch (111) consists of a pipe (1110) with a head (1111) and afoot (1112). The outer diameter of the head (1111) and the foot (1112)are larger than the outer diameter of the pipe (1110). The pipe (1110)extends through the connection channel (not shown in FIGS. 18 and 19).The connection channel corresponds to the connection channel (11) as forexample shown in FIGS. 1 and 2. The length of the ejector punch (111) islonger than the distance between the bottom of the drug containerreceptacle (5) (see FIG. 1) and the bottom of the flange (110). Theejector punch (111) is movably received in the connection channel. In aretracted state of the head (1111) of the ejector punch (111) rests onthe bottom of the drug container receptacle (5), in particular on thebottom of the receptacle chamber (52). The diameter of the head (1111)is larger than the diameter of the connection channel. In FIG. 19 theposition of the ejector punch (111) is shown in an extended state. Inthis extended state, the head (1111) of the ejector punch (111) is at aheight in the receptacle chamber (52) which corresponds to the height ofthe sealing rings (50). By moving the ejector punch (111) from theretracted state to the extended state, a vial or other drug container(not shown), which was held in the drug container receptacle (5) and wassealed on its outer circumference be the sealing rings (50), can bepushed away from the bottom of the receptacle chamber 52. Thereby,removing the drug container (3) after testing is simplified.

As can be derived from FIGS. 18 and 19, according to one embodiment, thehead (1111) and the foot (1112) of the ejector punch (111) have a slot(1113). The slot (1113) in the head (1111) is provided in the uppersurface of the head (1111) and the slot (1113) at the foot (1112) isprovided in the lower surface of the foot (1112). The slot (1113)extends over the diameter of the foot (1112) or the diameter of the head(1111), respectively. Thereby, fluid connection between the outercircumference of the head (1111) or foot (1113), respectively and thechannel (1114) of the pipe (1110) can be ensured, even if the head(1111) or foot (1113) are in contact with other elements. For example,air can be drawn into the drug container receptacle (5) through the pipe(1110), when the drug container (3) which was received and sealed indrug container receptacle (5) by the sealing rings (50) is pushed out ofthe drug container receptacle (5). Due to the air tightness obtained bythe sealing rings (50) moving the drug container (3) would not bepossible without allowing air to enter the drug container receptacle(5).

With this embodiment of the device, where an ejector punch (111) isprovided in the main body, the method according to the invention cancomprise a step of pushing the ejector punch (111) from a retractedstate to an extended state after the testing has been completed.Thereby, handling of the drug container (3) is facilitated. Theembodiment with the main body (10) having an ejector punch (111) ispreferably used for embodiments of the device (1), wherein the supportmember (70) and the movement member (71) are arranged above the drugcontainer (3), in particular outside of the drug container receptacle(5).

In FIG. 20 another embodiment of the main body (10) of a device isshown. This embodiment differs from the embodiment shown in FIGS. 18 and19 in that the device comprises an adapter cylinder (101). The adaptercylinder (101) has a cylindrical wall and is open at the top and closedat the bottom. In the bottom a through hole (1010) is provided. Theouter diameter of the adapter cylinder (101) corresponds to the innerdiameter of the drug container receptacle (5) in the main body (10). Inparticular, the outer diameter of the adapter cylinder (101) is equal orlarger than the inner diameter of the sealing rings (50) provided at theinner diameter of the drug container receptacle (5). Also at the innerdiameter of the adapter cylinder (101) sealing rings (50) are provided.The through hole (1010) has a diameter which is equal to or larger thanthe diameter of the channel (1114) in the ejector punch (111). Once theadapter cylinder (101) has been inserted into the drug containerreceptacle (5) of the main body (10), the adapter cylinder (101) acts asa receptacle chamber (52) for a drug container (3). Thereby, drugcontainers (3) of different sizes can be tested with the device, byselecting and inserting an adapter cylinder (101) of an appropriateinner diameter. As the device can include an ejector punch (111), theadapter cylinder (101) can be pushed out of the drug containerreceptacle (5) and can either be replaced by a different adaptercylinder (101) or a drug container (3) having a larger diameter may beinserted into the drug container receptacle (5) without an adaptercylinder (101). Also this embodiment with an adapter cylinder (101) ispreferably used for embodiments of the device (1), wherein the supportmember (70) for supporting the device (1) and the movement member (71)for supporting the device (1) are arranged above the drug container (3),in particular outside of the drug container receptacle (5).

In FIGS. 21 and 22 another embodiment of the main body (10) of thedevice is shown. This embodiment differs from the embodiment shown inFIGS. 18 and 19 in that a flooding ring (102) is attached to the mainbody (10). The flooding ring (102) has an attachment section (1020) anda flooding cylinder (1022) extending from the top of the attachmentsection (1020). The attachment section (1020) has an inner diameterwhich corresponds to the outer diameter of the main body (10) above thestep (1000). The height of the attachment section (1020) corresponds tothe distance of the step (100) of the main body (10) to the upper end ofthe main body (10). The flooding cylinder (1022) has an inner diameterwhich is smaller than the outer diameter of the main body (10) above thestep (1000). Thereby, the flooding cylinder (1022) rests on the uppersurface of the main body (10). At the inner diameter of the attachmentsection (1020) inner sealing rings (1021) are provided. In theembodiment shown in FIGS. 31 and 32 two inner sealing rings (1021) areprovided. By providing the flooding ring (102), a space above the upperend of the main body is created. In the upper end of the main body (10),the drug container receptacle (5) is formed.

With the drug container (3) having been introduced into the drugcontainer receptacle (5), the testing of the leakage between the rubberstopper (2) and the drug container (3) will be performed. If the sealingrings (50), which are provided in the drug container receptacle (5), donot sufficiently seal the lower part of the drug container receptacle(5) from the area above the sealing rings (50), air may be drawn intothe drug container receptacle (5), thereby decreasing the quality of thetest results. With the flooding ring (102) provided on the main body(10), it will be possible to fill the area above the upper end of themain body (1), with a liquid such as oil. Thereby, drawing in of airinto the lower part of the drug container receptacle (5) can be avoided.

According to another embodiment, the flooding ring may be integral withthe main body. In this case, the flooding ring can comprise only aflooding cylinder, which is extends from the surface of the upper end ofthe main body, where the drug container receptacle is formed.

In a particular embodiment of the invention, the device (1) according tothe invention comprises or is connectable to means for temperaturecontrol, in particular cooling means and/or heating means.

The cooling and/or heating means can be realized in form of an owndevice separate from device (1), for example a device for cooling and/orheating, into which the device (1) is inserted for cooling and/orheating during the test; or the cooling and/or heating means can becomprised in device (1).

In a particular embodiment, the device (1) is connectable to coolingmeans and the device (1) and the cooling means are connectable tocomputing means. In a different preferred embodiment, the device (1)additionally comprises cooling means and means to connect to a computingdevice.

In a preferred embodiment of the invention, the cooling means allow atleast the cooling of the closure system, that is of the connectionbetween the rubber stopper (2) and the drug container (3), constituentof regular opening (30) and rubber stopper (2), more preferably, thecooling means allows cooling of at least the drug container (3)comprising, even more preferably, the cooling means allow cooling of thechamber provided by the housing (9) and/or cooling of the drug containerreceptacle (5), and/or cooling of the main body (10).

In a preferred embodiment, the cooling means are adapted to providesequential, preferably continuous cooling at least of the aforementionedparts.

FIG. 14 shows an embodiment of device (1) with the housing (9), a handheld injector (17) for the supply of the test medium into the housing,device (1) with the connection channel (11) ending at the bottom ofdevice (1) in form of a tube with a flange 110 and the cooling and/orheating means implemented as a tempering device (19) being in form of aseparate device into which device (1) is inserted for cooling and/orheating during the test.

In a preferred embodiment the cooling means allow cooling totemperatures of at least −20° C. or lower, preferably at least −50° C.or lower, more preferably at least −80° C. or lower, particularlypreferably −100° C. or lower, more particularly −196° C. (77 K) orlower.

A computing system may be used which is configured to acquire any statusof and/or to control the device (1), and/or the device (1) and/or themeans for temperature control, with the device (1), and the device (1)and the means for temperature control as defined herein, also with alltheir embodiments.

The connection between a rubber stopper (2) and a corresponding drugcontainer (3) to be tested may be any suitable connection. Non-limitingexamples for a rubber stopper (2) comprise an elastomeric part which isresponsible for the actual closing or sealing of the regular opening(30) of the drug container (3) which needs to be closed. Examples forthe material of the elastomeric part are rubber or silicone. The form ofthe elastomeric part can be a plug or a lid. The connection between theregular opening (30) of the drug container (3) and the rubber stopper(2) can also comprise means for fixing the rubber stopper (2) to theregular opening (30) of the container (3), preferably by engagingbetween the rubber stopper (2) and the neck portion 33. An example forsuch means for fixing the rubber stopper (2) to the regular opening (30)of the container (3) are known to the skilled person under the term“blowback”.

With respect to the exemplary device (1) shown e.g. in FIG. 3 or 5, apressure difference between the interior 36 of the drug container (3)and the inside of the receptacle chamber 52 can for example be generatedby evacuating the inside of the receptacle chamber 52, by applyingpressure at the inside of the drug container (3), or by both measures,preferably by evacuating the inside of the receptacle chamber 52.

Furthermore, the method for leakage testing of a connection between arubber stopper (2) and a corresponding drug container (3) may be adestructive or non-destructive method. In a non-destructive method, thecontainer (3) may be filled with the testing gas before the container(3) is closed with the rubber stopper (2). In a destructive method, thecontainer may comprise the communication opening 31.

Preferably, detection of the test medium passing through a leakagebetween the regular opening (30) and the rubber stopper (2) is done inform of a concentration, of a flow rate or of an amount, more preferablyin form of a flow rate, of the test medium.

Preferably, the pressure inside the device (1), preferably in thepreferably sealed receptacle chamber 52, may be set to equal to or lessthan 100 mbar, more preferably equal to or less than 50 mbar, even morepreferably equal to or less than 25 mbar, especially equal to or lessthan 20 mbar, more especially equal to or less than 10 mbar, even moreespecially equal to or less than 5 mbar, in particular equal to or lessthan 1 mbar.

In a different embodiment of the invention, a pressure difference isgenerated, preferably by applying a vacuum to the inside of the device(1), that is in the receptacle chamber 52. Preferably, in suchembodiments, the vacuum in the inside of the device (1) is continuouslyreduced, while the pressure of the test medium inside the drug container(3) is maintained constant.

In a preferred embodiment, the constant pressure is atmosphericpressure.

Preferably, the drug container (3) is filled with a test mediumatmosphere, comprising at least 50%, even more preferably, at least 75%,especially at least 80%, more especially at least 85%, even moreespecially at least 90%, in particular at least 95%, of test medium, the% being % by volume based on the total volume of the atmosphere insideof the drug container (3).

The method according to the invention is suitable to be performedtemperature independent.

In one embodiment, the temperature is controlled in the method.

In particular, the method might be performed at constant temperature orat varying temperature. In particular the method is suitable to test theintegrity of the closure system, that is of the connection between therubber stopper (2) and the drug container (3), at typical storagetemperatures. Preferably, the temperature refers to the temperature ofthe receptacle chamber 52, of the main body (10), of an inner wall ofthe drug container receptacle (5), of the drug container (3), or of acombination thereof.

It is preferred that the temperature referred to herein refers at leastto the temperature of and/or around the neck portion 33 and/or theregular opening (30) of the container (3).

In a particular embodiment, the main body (10) and/or the drug containerreceptacle (5) are temperature controlled.

In some embodiments the method is performed at room temperature. In aspecific embodiment the method is performed at 18 to 27° C., preferablyat 20 to 26° C., more preferably at 22 to 25° C., even more preferablyat about 24 to 25° C.

The method might be performed at higher or lower temperatures than roomtemperature. In particular, the method might be performed at lowertemperatures than room temperature. In some embodiments, the method isperformed at 20° C. or less, in other embodiments at 15° C. or less, infurther embodiments at 10° C. or less.

In a specific embodiment of the invention, the method is performed at 0°C. to 10° C., preferably 2° C. to 8° C., more preferably 3° C. to 6° C.,particularly preferably at 4° C. to 5° C. In a particular embodiment,the method is performed at 4° C.

In some embodiments of the invention, the method is performed belowfreezing temperature of water. In some embodiments the method isperformed at 0° C. or below. In a specific embodiment, the method isperformed at −4° C., −5° C., −6° C., −7° C., −8° C., −9° C., −10° C. orbelow. In some embodiments, the method is performed at −15° C. or below,in particular −20° C. or below.

The method may be performed at even lower temperatures. In someembodiments of the invention, the method is performed at −30° C., −40°C., −50° C., −60° C., −70° C., −80° C., −90° C., −100° C. or below. In aspecific embodiment, the method is performed at a temperature of from−70° C. to −90° C., preferably of from −75° C. to −85° C., morepreferably the method is performed at −80° C.

If the cooling is based on a mixture of dry ice and isopropyl alcohol,the method might be performed at about −77° C.

If the cooling is based on liquid nitrogen, the method might beperformed at about −196° C.

Optionally, the means for temperature control are adapted such that thetemperature can be adjusted to more or less any specific chosentemperature.

The method may also be performed at varying temperatures to determinethe suitability for the closure system that is of the connection betweenthe rubber stopper (2) and the drug container (3), for different storageand usage conditions. In such an embodiment, the method additionallycomprises the step of varying the temperature.

In a specific embodiment, the invention relates to a method for testingthe temperature dependence of the integrity of the connection betweenthe rubber stopper (2) and the corresponding drug container (3).

Thereby, the method further may comprise the additional step ofcontrolling the temperature, preferably at for a predetermined period oftime. More preferably, the temperature is controlled over the entiretime of testing.

In some embodiments of the invention, the temperature is variedsequentially. In other embodiments the temperature is variedcontinuously. In a preferred embodiment, the temperature is variedcontinuously, with a linear change of temperature. In a specificembodiment, the temperature is continuously lowered with a linear rate.

The method may optionally comprise the step of identifying at least onethreshold temperature, until which safe handling and/or storing of thedrug container (3) without affecting the integrity of the connectionbetween rubber stopper (2) and regular opening (30) is provided.

In one embodiment, the method is performed at a predeterminedtemperature. Therefore, a tempering medium, preferably a temperingliquid may be provided, wherein preferably, the tempering medium may beprovided with a predefined temperature.

According to some preferred embodiments, the receptacle (5) optionallyforms a tempering gap 18, which may be located between the inner wall ofthe container receptacle (5) and the drug container (3). Preferably, thetempering gap 18 is located opposite to the connection channel (11) withrespect to a sealing (50).

In some embodiments of the invention, the tempering medium may be ledinto the tempering gap 18; see for example FIG. 17.

According to a preferred embodiment, the device comprises means fortemperature control in the form of a separate tempering device.Preferably the tempering device is formed such the main body (10) and/orthe housing (9) can be inserted into the tempering device.

In some embodiments, the tempering device is a double walled device,wherein preferably the temperature may be controlled by leadingtempering medium through the double walled wall at the desiredtemperature.

A schematic view of a device (1) comprising a tempering device (19) canbe seen in FIGS. 15 and 16.

According to another preferred embodiment, the device (1) may compriseone or more temperature sensors and/or means for sensor positioningmeans adapted for positioning one or more temperature sensors intodevice (1).

In one embodiment, one or more temperature sensors can be placed in orare located in the drug container (3) and/or in the device (1).

The invention further relates to a temperature sensor for use with adevice (1) as defined herein, also with all its embodiments.

In one embodiment, the device (1) comprises or is used with a holdingdevice (120) for holding one or more temperature sensors 12 within thedrug container (3), wherein preferably, the holding device (120) can beplaced in or is located in the drug container (3).

In FIGS. 17 and 18, a schematic example of holding device (120) can beseen wherein a support member functioning analogously to the embodimentshown in FIGS. 10 and 11 also functions as the holding device (120). Ingeneral, a holding device (120) according to the invention comprises atleast one opening (121), which allows the insertion of a temperaturesensor (12). In some embodiments, holding device (120) has a pluralityof openings (121). In some embodiments holding device (120) comprises atleast one temperature sensor (12) or has means for placing at least onetemperature sensor into holding device (120).

The holding device (120) may preferably be adapted to a specific type ofdrug container (3), comprising means for measuring the temperature ofholding device (120) and comprising at least one means for passing atest medium into said drug container (3).

In some embodiments, said opening (121) can be filled with temperingmedium to allow for accurate temperature measurement, for example whentempering medium is filled in the opening (121) then tempering mediummediates the passing of the temperature from holding device (120) to atemperature sensor inserted in the opening (121).

The holding device (120) may be made from any suitable material but ispreferably made of metal.

In some embodiments holding device (120) may be configured to beinserted into the drug container (3). At least in this case, preferablythe holding device (120) may comprise a passing section 122 for allowingtest medium to pass into the drug container (3), for example a pluralityof channels or holes extending through the holding device (120).

The holding device (120) may also comprises or can be connected to adevice for temperature control.

The invention further relates to a computer program comprisinginstructions which when the program is executed by a computer, causesthe computer to acquire any status of and/or to cause the device (1) toperform any of steps e), f) and g) of any of the methods of theinvention, with the device (1) and the methods of the invention asdescribed herein, also with all their embodiments.

Preferably, the computer program comprises instructions to acquire anystatus of and/or to cause the device (1) comprising means fortemperature control, to perform any of the methods of the invention,with the device (1), the methods of the invention and the means fortemperature control as described herein, also with all theirembodiments.

The invention further relates to a computer-readable medium havingstored thereon the computer program as defined herein, also with all itsembodiments.

Except for embodiments and features described herein, the detection unit6 according to the present invention might be based on a testing deviceknown in the prior art. Such testing devices for leak detection incontainer closure integrity testing are known to the person skilled inthe art. In general, these testing devices are based on massspectrometric He detection.

It will be obvious for a person skilled in the art that theseembodiments and items only depict examples of a plurality ofpossibilities. Hence, the embodiments shown here should not beunderstood to form a limitation of these features and configurations.Any possible combination and configuration of the features describedherein can be chosen according to the scope of the invention.

LIST OF REFERENCE NUMERALS

-   1 device-   2 rubber stopper-   20 collar-   21 insertion section-   3 drug container-   30 regular opening-   31 communication opening-   310 inner wall-   32 opening direction-   33 neck portion-   34 outer diameter-   35 shoulder-   36 interior-   37 collar-   4 test medium-   5 drug container receptacle-   50 sealing-   52 receptacle chamber-   53 guiding-   6 detection unit-   70 support member-   700 thread-   702 diameter of collar section-   703 support section-   704 abutment section-   705 contact area-   71 movement member-   710 thread-   713 collar section-   715 threaded rod-   716 tooth-   717 engagement section-   718 contact area-   719 alignment section-   72 movement direction-   73 linear travel-   75 distance-   8 movement unit-   80 gear wheel-   9 housing-   10 main body-   100 positioning section-   1000 step-   101 adaptor cylinder-   1010 through hole-   1011 sealing ring-   102 flooding ring-   1020 attachment section-   1021 inner sealing ring-   1022 flooding cylinder-   11 connection channel-   110 flange-   111 ejector punch-   1110 pipe-   1111 head-   1112 foot-   1113 slot-   1114 channel-   12 temperature sensor-   120 holding device-   121 opening-   13 test medium supply-   15 positioning unit-   16 down-holding unit-   17 injector-   18 gap-   19 tempering device

The invention claimed is:
 1. A device for leakage testing with provisionof a displacement of a rubber stopper, which is inserted into a regularopening of a drug container, relative to the drug container in anopening direction for leakage testing of a connection between the rubberstopper and the corresponding drug container, the device comprising atest medium supply for exposing a connection region of the drugcontainer and the rubber stopper to a test medium, a detection unit fordetecting the presence of test medium that has passed through theregular opening of the drug container due to a leakage between theconnection of the rubber stopper and the drug container, a supportmember, a movement member, and a drug container receptacle with the drugcontainer received in the drug container receptacle, wherein the supportmember supports the movement member, the movement member is movablerelative to the support member in a movement direction which is parallelto the opening direction of the rubber stopper, and the movement memberextends into the drug container receptacle for the displacement of therubber stopper such that part of the movement member is inserted intothe drug container through a communication hole which is provided at thedrug container apart from its regular opening for enabling fluidcommunication of the interior of the drug container and the exterior ofthe drug container.
 2. The device according to claim 1, wherein the drugcontainer is a vial or a cartridge.
 3. The device according to claim 1,wherein, the support member and the movement member comprisecomplementarily formed threads engaging with each other, which areconfigured such that a rotation of the movement member relative to thesupport member results in a linear travel of the movement memberrelative to the support member in the movement direction.
 4. The deviceaccording to claim 1, wherein the support member comprises an internalthread and the movement member comprises a threaded rod, wherein thethread of the threaded rod is in engagement with the internal thread ofthe support member.
 5. The device according to claim 1, wherein the drugcontainer receptacle comprises a communication opening for enablingfluid communication of the exterior of the drug container receptaclewith an interior of the drug container receptacle.
 6. The deviceaccording to claim 5, wherein the device further comprises a housingwith an opening into which test medium may be introduced into a chamberprovided by the housing.
 7. The device according to claim 6, wherein thehousing comprises the test medium supply adapted to introduce the testmedium into the housing.
 8. The device according to claim 5, wherein thedevice comprises or is connectable to means for temperature control. 9.A method for leakage testing of a connection between the rubber stopperand a corresponding drug container, comprising the steps of: a)providing a device according to claim 1, b) providing a drug containerwith a communication opening for enabling fluid communication of anexterior of the drug container with the interior of the drug containerapart from its regular opening, c) closing the regular opening of thedrug container with the rubber stopper, d) inserting the drug containerinto the drug container receptacle of the device, e) exposing either theexterior of the drug container or, alternatively, the interior of thedrug container at least at a connection region of the drug container andthe rubber stopper inserted into the regular opening of the drugcontainer to a test medium, and f) displacing the rubber stopperrelative to the drug container in an opening direction for a chosendistance while measuring any presence of the test medium either in theinterior or, alternatively, in the exterior of the drug container thathas passed through the regular opening, wherein g) the rubber stopper isdisplaced relative to the drug container by means of the movement memberof the device.
 10. The method according to claim 9, wherein the methodfurther comprises acquiring the linear travel of the rubber stopper orof the movement member, respectively.
 11. The method according to claim10, wherein the linear travel is determined by means of detecting thecumulated angle of rotation in combination with a lead of the threads.12. The method according to claim 9, further comprising a non-transitorycomputer-readable medium having stored thereon a computer program,wherein, when the computer program is executed by a computer, causes thedevice to perform any of steps e), f), and g) of the method.
 13. Anon-transitory computer-readable medium having stored thereon a computerprogram which, when the computer program is executed by a computer,causes a device to perform any of steps e), f), and g) of a method;wherein the device is a device for leakage testing with provision of adisplacement of a rubber stopper, which is inserted into the a regularopening of a drug container, relative to the drug container in anopening direction for leakage testing of a connection between the rubberstopper and the corresponding drug container, the device comprising atest medium supply for exposing a connection region of the drugcontainer and the rubber stopper to a test medium, a detection unit fordetecting the presence of test medium that has passed through theregular opening of the drug container due to a leakage between theconnection of the rubber stopper and the drug container, a supportmember, a movement member, and a drug container receptacle with the drugcontainer received in the drug container receptacle; wherein the supportmember supports the movement member, the movement member is movablerelative to the support member in a movement direction which is parallelto the opening direction of the rubber stopper, and the movement memberextends into the drug container receptacle for the displacement of therubber stopper such that part of the movement member is inserted intothe drug container through a communication hole which is provided at thedrug container apart from its regular opening for enabling fluidcommunication of the interior of the drug container and the exterior ofthe drug container; the method is a method for leakage testing of aconnection between the rubber stopper and a corresponding drugcontainer, comprising the steps of: a) providing the device, b)providing a drug container with a communication opening for enablingfluid communication of an exterior of the drug container with theinterior of the drug container apart from its regular opening, c)closing the regular opening of the drug container with the rubberstopper, d) inserting the drug container into the drug containerreceptacle of the device, e) exposing either the exterior of the drugcontainer or, alternatively, the interior of the drug container at leastat a connection region of the drug container and the rubber stopperinserted into the regular opening of the drug container to a testmedium, and f) displacing the rubber stopper relative to the drugcontainer in an opening direction for a chosen distance while measuringany presence of the test medium either in the interior or,alternatively, in the exterior of the drug container that has passedthrough the regular opening, wherein g) the rubber stopper is displacedrelative to the drug container by means of the movement member of thedevice.